Positron emission tomography (PET) is a nuclear medicine imaging technique that produces images of functional processes of the body. Radiotracers are used in PET as diagnostic tools and to image tissue concentration of molecules of interest.
The development of molecular imaging biomarkers is closely related to the development of therapeutic molecules. Among the potential targets, kinases offer a lot of advantages and notably (i) they play a central role in cellular regulation, (ii) numerous kinase-specific small molecule libraries exist in biotech and pharma industry, (iii) several kinase-targeted therapies are used in clinic (imatinib, sorafenib, sunitinib . . . ) with application across a variety of therapeutic indications. Among the kinases, the epidermal growth factor receptor (EGFR) is an established target for the treatment of advanced non-small cell lung cancer (NSCLC). Three EGFR tyrosine kinase inhibitors (TKIs) gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®) have already been approved for treatment of NSCLC, and third generation of molecules is under clinical development. Multiple randomized controlled trials have confirmed the association between the presence of activating EGFR mutations (exon 19 del. or L858R point mutation) and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR-mutation-positive tumors (10 to 15%) (Sebastian et al., 2014, European Respiratory Review, 23 (131): 92-105). Unfortunately the majority of patients will develop a resistance to the TKI in the long term (6-12 months) despite initially good control. If the mechanism of resistance are not yet fully characterized, most patients (50%) will acquire an additional T790M mutation located in exon 20 of EGFR (Pao et al., 2005, PLoS Medicine, 2(3): e73; Yun et al., 2008, PNAS 105 (6): 2070). Other subgroups of patients will show a resistance due to the amplification of MET protoongene which is responsible for up to 20% of relapsing patients or inactivation of the phosphatase and tensin homolog (PTEN) tumor suppressor gene, leading to the activation of phosphatidylinositol 3-Kinase (PI3K)/AKT pathway (Sequist et al., 2011, Science translational medicine, 3(75): 75ra26). The lack of an established therapeutic option for NSCLC patients who have progressive disease after EGFR-TKIs failure poses a great challenge to physicians in terms of how to best manage this growing group of patients.
PET-imaging with radiolabeled TKIs (TKI-PET) can provide a tool to determine and predict responsiveness to EGFR TKIs in vivo. There is a clinical need for non-invasive technology to early evaluate the treatment responsiveness and determine the spatial and temporal acquisition of molecular mutation leading to tumor resistance. TKI-PET is a potential personalized medicine tool that will guide the physicians to adapt the treatment of their patients, choosing the best treatment or combination of treatments according the spatial and temporal evolution of tumor resistance and its molecular causality.
The present invention provides a new radiolabeled (18-Fluor) compound targeting EGFR evaluated in vitro and in preclinical imaging study. This compound could be useful to predict the activity of EGFR, correlated with its mutational status, and follow-up of this activity in tumors treated by EGFR targeted therapies. Uptake of radiolabeled compound in the tumors can be determined with PET. Examples of this principle with 11C-erlotinib or 18F-afatinib are published respectively by Memon et al in British Journal of Cancer, 2011, 1850-1855 and by Slobbe et al in Nuclear Medicine and Biology 41 (2014) 749-757. Macrocyclic quinazoline derivatives have already been described to be suitable anti-proliferative agents (WO2004105765), however, we have now surprisingly found that the particular compounds of the invention, are very suitable PET tracers.
The present invention aims to provide radioligands selective for EGFR (erbB1) as PET tracer for in vivo diagnosis, preclinical and clinical tumour imaging, patient stratification on the basis of mutational status of EGFR, and tumour response to therapeutic treatments.